The overall goal of this project is to support my continued professional development as an independent patient-oriented investigator and successfull mentor. My recent research focus has been to establish and validate optimal biochemical endpoints for the therapy of acromegaly. In these efforts, I have established a uniquely large cohort of patients, re-defined its biochemical criteria based on highly sensitive GH and IGF-I measurements and investigated novel therapeutic approaches to this disease. From these studies, we recognized the need to validate the biochemical endpoints for treatment against clinical disease activity in order to ensure truly "normal" clinical GH/IGF-I status. The scientific aims of this application correlate modern biochemical markers with short and long-term clinical outcomes and with metabolic and clinical disease activity in our cohort. The first 4 aims, funded by R01 DK06420 for which I am the PI, investigate the use of body composition to gauge disease activity, therapy with the novel GH receptor antagonist, pegvisomant, and the effect of dysregulated ghrelin secretion on biochemical and clinical disease activity markers in acromegaly. Two new aims extend those of my R01, investigating, in Aim 5, IGF-I levels as a markers of insulin sensitivity and body composition in acromegaly and in Aim 6, IGF-I as a marker of cardiovascular structure and function during therapy with the GH receptor anagonist, pegvisomant. These studies aim to improve our understanding of the optimal therapeutic endpoints and, in particular, our serum IGF-I goals for the treatment of acromegaly. My productive, ongoing, NIH funded clinical research program and 12 years of experience in patient-oriented research make me well suited to receive the K24 award. The additional funds provided by the K24 would allow me to raise my effort of NIH research support commensurate with the amount of time I currently commit to patient-oriented research and mentoring and also allow me to continue to expand in both these areas. The institutional environment at Columbia University, with a strong and diverse Endocrine Division, GCRC, Diabetes and Obesity Research Centers, is ideal for attracting fellows and conducting our research. The Mid-career Investigator Award in Patient Oriented Research is an ideal mechanism to ensure the necessary support I need to reduce clinical and administrative responsibilities, and ensure my continued success as a mentor and clinical researcher.